We have undertaken a program that is aimed at determining, on a molecular level, those genetic alterations in primary breast tumor DNA that have a statistically significant association with the patients history, characteristics of the tumor, and the patients prognosis. The most frequent type of mutation is loss of heterozygosity (LOH) at specific regions of the cellular genome in tumor DNA. Approximately 20 such regions have been identified in breast tumor DNAs. Several studies indicate that the short arm of chromosome 17 is one of the most frequently altered regions in sporadic breast carcinomas (45-60%). In our study the 17p13.3-ter region in tumor DNA of 152 patients, along with their matching normal lymphocyte DNAs, have been mapped with four markers (D17S5,D17S379, ABR and D17S34), spanning nearly 3 cM of the telomer. High levels of loss of these distal markers on 17p13.3 are independent of TP53 mutations and are associated with tumor cell proliferation. A follow up period of over 7 years demonstrated that loss of these markers correlates both with disease free (p=0.004) and overall survival (p=0.007). In addition we found that for disease free survival the prognostic power of this genetic alteration is only second to axillary lymph node involvement (3.1 R.R. versus 6.3 R.R.), and more significant than the mutational status of TP53 (R.R.1.6). Our results are further evidence of the presence, within the region, of at least a second tumor suppressor gene distal to TP53, that might be targeted by deletions. - Human breast cancer, Loss of heterozygosity, Mutations in sporadic breast tumors,